BEVESPI AEROSPHERE (glycopyrrolate and formoterol fumarate) Inhalation Aerosol is a pressurized metered-dose inhaler that contains a combination of micronized glycopyrrolate, an anticholinergic, and micronized formoterol fumarate, a long-acting beta 2 -adrenergic agonist, for oral inhalation. Glycopyrrolate is a quaternary ammonium salt with the following chemical name: ( RS )-[3-( SR )-Hydroxy-1,1-dimethylpyrrolidinium bromide] α-cyclopentylmandelate. Glycopyrrolate is a powder that is freely soluble in water. The molecular formula is C 19 H 28 BrNO 3 , and the molecular weight is 398.33 g/mol. The structural formula is as follows: Glycopyrrolate contains two chiral centers (denoted by * in structure above) and is a racemate of a 1:1 mixture of the R,S and S,R diastereomers. The active moiety, glycopyrronium, is the positively charged ion of glycopyrrolate. Formoterol fumarate has the chemical name N -[2-Hydroxy-5-[(1RS)-1-hydroxy-2-[[(1RS)-2-(4-methoxyphenyl)-1- methylethyl]-amino] ethyl]phenyl] formamide, €-2-butenedioate dihydrate. Formoterol fumarate is a powder that is slightly soluble in water. The molecular formula is (C 19 H 24 N 2 O 4 ) 2 .C 4 H 4 O 4 .2H 2 O and the molecular weight is 840.91 g/mol. The structural formula is as follows: Formoterol fumarate contains two chiral centers (denoted by * in structure above), and consists of a single enantiomeric pair (a racemate of R,R and S,S). BEVESPI AEROSPHERE is formulated as a hydrofluoroalkane (HFA 134a) propelled pressurized metered dose inhaler containing 120 inhalations. The canister has an attached dose indicator and is supplied with a white plastic actuator body and mouthpiece with an orange dust cap. After priming each actuation of the inhaler meters 10.4 mcg of glycopyrrolate (equivalent to 8.3 mcg of glycopyrronium) and 5.5 mcg of formoterol fumarate from the valve which delivers 9 mcg of glycopyrrolate (equivalent to 7.2 mcg of glycopyrronium) and 4.8 mcg of formoterol fumarate from the actuator. The actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between actuation of the device and inspiration through the delivery system. BEVESPI AEROSPHERE also contains porous particles that form a cosuspension with the drug crystals. The porous particles are comprised of the phospholipid, 1,2-Distearoyl- sn -glycero-3-phosphocholine (DSPC), and calcium chloride. Porous particles and HFA 134a are excipients in the formulation. The Structural Formula of Glycopyrrolate contains two chiral centers (denoted by * in structure above) and is a racemate of a 1:1 mixture of the R,S and S,R diastereomers. The Structural Formula of Formoterol fumarate contains two chiral centers (denoted by * in structure above), and consists of a single enantiomeric pair (a racemate of R,R and S,S).

BEVESPI AEROSPHERE is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). Limitations of Use: BEVESPI AEROSPHERE is not indicated for the relief of acute bronchospasm or for the treatment of asthma . BEVESPI AEROSPHERE is a combination of glycopyrrolate, an anticholinergic, and formoterol fumarate, a long-acting beta 2 -adrenergic agonist (LABA) indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). Limitations of Use : Not indicated for the relief of acute bronchospasm or for the treatment of asthma. ( 1 , 5.1 , 5.2 )

Inhalation aerosol: pressurized metered dose inhaler that delivers 9 mcg of glycopyrrolate and 4.8 mcg of formoterol fumarate per inhalation. • Inhalation aerosol: pressurized metered dose inhaler containing a combination of glycopyrrolate (9 mcg) and formoterol fumarate (4.8 mcg) per inhalation.

• For oral inhalation only. • Maintenance treatment of COPD: 2 inhalations of BEVESPI AEROSPHERE twice daily by oral inhalation

Recommended Dosage and Administration The recommended dosage of BEVESPI AEROSPHERE is glycopyrrolate 18 mcg and formoterol fumarate 9.6 mcg (administered as two inhalations of BEVESPI AEROSPHERE [glycopyrrolate/formoterol fumarate 9 mcg/4.8 mcg]) twice daily in the morning and in the evening by oral inhalation. Do not take more than two inhalations twice daily

Preparation Prime BEVESPI AEROSPHERE before using for the first time. Priming BEVESPI AEROSPHERE is essential to ensure appropriate drug content in each actuation. To prime BEVESPI AEROSPHERE, release 4 sprays into the air away from the face, shaking well before each spray. BEVESPI AEROSPHERE must be re-primed when the inhaler has not been used for more than 7 days. To re-prime BEVESPI AEROSPHERE, release 2 sprays into the air away from the face, shaking well before each spray

Dose Counter The canister has an attached dose indicator, which indicates how many inhalations remain. The dose indicator display will move after every tenth actuation. When nearing the end of the usable inhalations, the color behind the number in the dose indicator display window changes to red. BEVESPI AEROSPHERE should be discarded when the dose indicator display window shows zero.

• LABA as monotherapy (without an inhaled corticosteroid) for asthma increases the risk of serious asthma-related events. • Do not initiate in acutely deteriorating COPD or to treat acute symptoms. • Do not use in combination with an additional therapy containing a LABA because of risk of overdose. • If paradoxical bronchospasm occurs, discontinue BEVESPI AEROSPHERE and institute alternative therapy. • Use with caution in patients with cardiovascular disorders. • Worsening of narrow-angle glaucoma may occur. Use with caution in patients with narrow-angle glaucoma and instruct patients to contact a physician immediately if symptoms occur. • Worsening urinary retention may occur. Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction and instruct patients to contact a physician immediately if symptoms occur. • Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. • Be alert to hypokalemia and hyperglycemia. 5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death • The safety and efficacy of BEVESPI AEROSPHERE in patients with asthma have not been established. BEVESPI AEROSPHERE is not indicated for the treatment of asthma . • Use of LABA as monotherapy [without inhaled corticosteroids (ICS)] for asthma is associated with an increased risk of asthma-related death. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone. • A 28-week, placebo-controlled US trial comparing the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs. 3/13,179 in subjects treated with placebo; RR 4.37, 95% CI: 1.25, 15.34). The increased risk of asthma-related death is considered a class effect of LABAs, including formoterol fumarate, one of the active ingredients in BEVESPI AEROSPHERE. • No trial adequate to determine whether the rate of asthma-related deaths is increased in patients treated with BEVESPI AEROSPHERE has been conducted. • Available data do not suggest an increased risk of death with use of LABA in patients with COPD

Deterioration of Disease and Acute Episodes BEVESPI AEROSPHERE should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. BEVESPI AEROSPHERE has not been studied in patients with acutely deteriorating COPD. The use of BEVESPI AEROSPHERE in this setting is inappropriate. BEVESPI AEROSPHERE should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. BEVESPI AEROSPHERE has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled short-acting beta 2 -agonist. When beginning BEVESPI AEROSPHERE, patients who have been taking inhaled, short-acting beta 2 -agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular use of these medicines and use them only for symptomatic relief of acute respiratory symptoms. When prescribing BEVESPI AEROSPHERE, the healthcare provider should also prescribe an inhaled, short acting beta 2 -agonist and instruct the patient on how it should be used. Increasing inhaled beta 2 -agonist use is a signal of deteriorating disease for which prompt medical attention is indicated. COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If BEVESPI AEROSPHERE no longer controls the symptoms of bronchoconstriction, or the patient’s inhaled, short-acting beta 2 -agonist becomes less effective, or the patient needs more inhalations of short-acting beta 2 -agonist than usual, these may be markers of deterioration of disease. In this setting, a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dosage of BEVESPI AEROSPHERE beyond the recommended dose is not appropriate in this situation

Avoid Excessive Use of BEVESPI and Avoid Use with Other Long-Acting Beta 2 -Agonists As with other inhaled medicines containing beta 2 -agonists, BEVESPI AEROSPHERE should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing LABAs, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic medicines. Patients using BEVESPI AEROSPHERE should not use another medicine containing a LABA for any reason

Paradoxical Bronchospasm As with other inhaled medicines, BEVESPI AEROSPHERE can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with BEVESPI AEROSPHERE, it should be treated immediately with an inhaled, short-acting bronchodilator, BEVESPI AEROSPHERE should be discontinued immediately, and alternative therapy should be instituted

Hypersensitivity Reactions including Anaphylaxis Immediate hypersensitivity reactions have been reported after administration of glycopyrrolate or formoterol fumarate, the components of BEVESPI AEROSPHERE. If signs suggesting allergic reactions occur, in particular, angioedema (including difficulties in breathing or swallowing, swelling of tongue, lips, and face), urticaria, or skin rash, BEVESPI AEROSPHERE should be stopped at once and alternative treatment should be considered

Cardiovascular Effects Formoterol fumarate, like other beta 2 -agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, or symptoms . If such effects occur, BEVESPI AEROSPHERE may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown. Therefore, BEVESPI AEROSPHERE should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension

Worsening of Narrow-Angle Glaucoma BEVESPI AEROSPHERE should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos, or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop

Worsening of Urinary Retention BEVESPI AEROSPHERE should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a physician immediately should any of these signs or symptoms develop

Coexisting Conditions BEVESPI AEROSPHERE, like all medications containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta 2 -agonist albuterol, when administered intravenously, have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis

Hypokalemia and Hyperglycemia Beta 2 -agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects . The decrease in serum potassium is usually transient, not requiring supplementation. Beta 2 -agonist medicines may produce transient hyperglycemia in some patients. In two clinical trials of 24-weeks and a 28-week safety extension study evaluating BEVESPI AEROSPHERE in subjects with COPD, there was no evidence of a treatment effect on serum glucose or potassium.

No formal drug interaction studies have been performed with BEVESPI AEROSPHERE. • Other adrenergic drugs may potentiate effect: Use with caution • Xanthine derivatives, steroids, diuretics or non-potassium sparing diuretics may potentiate hypokalemia or ECG changes. Use with caution. • Diuretics: Use with caution. Electrocardiographic changes and/or hypokalemia associated with non-potassium sparing diuretics may worsen with concomitant beta 2 -agonists. • Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of formoterol fumarate on cardiovascular system. • Beta-blockers: Use with caution and only when medically necessary. • Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administrations of BEVESPI AEROSPHERE with other anticholinergic-containing drugs

Adrenergic Drugs If additional adrenergic drugs are to be administered by any route, they should be used with caution because the sympathetic effects of formoterol, a component of BEVESPI AEROSPHERE, may be potentiated

Xanthine Derivatives, Steroids, or Diuretics Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate any hypokalemic effect of beta 2 adrenergic agonists such as formoterol, a component of BEVESPI AEROSPHERE

Non-Potassium Sparing Diuretics The ECG changes and/or hypokalemia that may result from the administration of non-potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta 2 -agonists, especially when the recommended dose of the beta 2 -agonist is exceeded. Approximately 17% of subjects were taking non-potassium sparing diuretics during the two 24-week placebo-controlled trials in subjects with COPD. The incidence of adverse events in subjects taking non-potassium-sparing diuretics was similar between BEVESPI AEROSPHERE and placebo treatment groups. In addition, there was no evidence of a treatment effect on serum potassium with BEVESPI AEROSPHERE compared to placebo in subjects taking non-potassium sparing diuretics during the two 24-week trials. However, caution is advised in the coadministration of BEVESPI AEROSPHERE with non-potassium-sparing diuretics

Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, QTc Prolonging Drugs BEVESPI AEROSPHERE, as with other beta 2 -agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants or other drugs known to prolong the QTc interval because the action of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval may be associated with an increased risk of ventricular arrhythmias

Beta-Blockers Beta-adrenergic receptor antagonists (beta-blockers) and BEVESPI AEROSPHERE may interfere with the effect of each other when administered concurrently. Beta-blockers not only block the therapeutic effects of beta 2 -agonists, but may produce severe bronchospasm in COPD patients. Therefore, patients with COPD should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-blockers in patients with COPD. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution

Anticholinergics There is a potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of BEVESPI AEROSPHERE with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects .